Caveolin-1 (cav-1) has been identified in many cell types including adipocytes, vascular endothelial cells and smooth muscle cells - where it modulates enzyme and receptor signaling and is involved in both vascular function and insulin sensitivity. Furthermore, there is a clear association between insulin resistance and hypertension; however, the genetic underpinnings of their association are yet to be discovered. Recently, we identified in hypertensive but not normotensive humans, a novel association between cav-1 gene variants and insulin resistance (IR), as well as an altered vascular response to angiotensin II. Cav-1 knockout (KO) mice also displayed IR, and altered vasorelaxation and vasoconstriction; moreover, these vascular abnormalities were dependent on the presence of the endothelium and on the activation state of the mineralocorticoid receptor (MR). Thus, based on our parallel findings in animals and humans, the central hypothesis for the current proposal is that genetic variation in the cav-1 gene is a major determinant of vascular dysfunction in hypertensive and insulin resistant individuals, and that cav-1 - via its interaction with the MR - modulates endothelial events critical for the physiologic vascular response. The overall goal of the present proposal is to expand on our novel preliminary findings in three ways. First, we will determine whether genetic variation at the cav-1 locus is a determinant of vascular dysfunction phenotypes in vivo in hypertensive humans with IR. Second, we will assess in vivo in endothelium-specific cav-1 KO mice, the hypothesis that endothelial cav-1 and MR are critical modulators of vascular function. Third, we will determine in vivo whether insulin sensitization (by metformin) will affect the vascular dysfunction phenotype in the generalized cav-1 KO model. Thus, the current application begins to address the role of cav-1 as one of the genetic underpinnings of vascular dysfunction in IR hypertensive individuals, and explores mechanisms by which endothelial cav-1 maintains vascular tone. The findings resulting from this proposal could lead to improved prevention and differential treatment options for patients with IR and hypertension. PUBLIC HEALTH RELEVANCE: Caveolin-1 is a protein that interacts with important signaling mechanisms inside the cells, including the ability to regulate blood vessel function and to lower blood sugar levels in response to insulin. Recently we have determined that caveolin-1 deficiency is associated with inability to respond to insulin (insulin resistance) and with reduced contractility of the blood vessels. This project will assess the mechanisms by which genetic variation in caveolin-1 can lead to changes in blood vessel function in individuals with high blood pressure and insulin resistance.